Calciphylaxis

Updated: Aug 02, 2018
  • Author: Julia R Nunley, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Calciphylaxis is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia in 1898. However, the significance of this relationship became uncertain when vascular calcification was subsequently shown to be prevalent in uremia, yet the syndrome of vascular calcification with cutaneous necrosis was less common. [1]

In 1962, Selye [2] constructed an experimental model and was able to precipitate systemic calcification, somewhat analogous to this syndrome, in nephrectomized rats. He was the first to coin the term calciphylaxis to characterize this enigma. Over the years, many other names have been suggested to characterize the pathogenic process, which has remained elusive. Interestingly, the clinical importance of this syndrome was not recognized until a 1976 report by Gipstein et al. [3] Since then, a multitude of case reports of calciphylaxis have documented data outlining its morbidity and therapeutic dilemmas, as well as a quest to better understand its etiology and pathogenesis. Unfortunately, it remains a conundrum. [4]

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Pathophysiology

The pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic renal failure, obesity, diabetes mellitus, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product, secondary hyperparathyroidism, and perhaps a variety of hypercoagulable states. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.

Using a rat model, Selye [2] demonstrated that a series of events might be necessary for the formation of calciphylaxis. He defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time. Experimental sensitizing events and agents included nephrectomy and exposure to parathyroid hormone (PTH) and vitamin D. Substances used as challengers included egg albumin and metallic salts. Calciphylaxis was the end result. [5]

Although extrapolation of animal data to humans is conjectural, it seems to be true that serial events, most consistently involving renal failure–induced abnormalities in calcium homeostasis, are required to occur over time for calciphylaxis to develop. The cause of calciphylaxis has been elusive, most likely because it is the common endpoint of a heterogeneous group of disorders.

Many molecular and cytochemical factors have been identified as crucial in bone metabolism. The receptor activator of nuclear factor-kB (RANK), RANK ligand, and osteoprotegerin appear to regulate skeletal and extraskeletal mineralization. [6, 7] Uremia-induced defects in this system may predispose to calciphylaxis. [8] Corticosteroids, aluminum, hyperparathyroidism, liver disease, warfarin therapy, and a variety of inflammatory processes all can alter this balance and promote vascular calcification. [9, 10] Chronic inflammatory conditions may predispose to calciphylaxis by reducing serum levels of fetuin-A, an important inhibitor of calcification produced in the liver. [11, 12, 13] Other authors have recently suggested that calciphylaxis is an active form of osteogenesis with up-regulation of bone morphogenic protein 2 (BMP-2), Runx2, its target gene, and its indirect antagonist sclerostin. [14]

Many investigators have noted that vascular occlusion and thrombosis are uniformly present and result in cutaneous ischemia [15, 16, 17] ; however the factors associated with thrombosis are not uniform.

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Etiology

Disorders associated with the development of calciphylaxis include the following [3, 6, 22, 23, 24] :

  • Common associations include chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, and vascular calcification.

  • Speculative associations include aluminum toxicity, coagulation abnormalities, and iron dextran infusion.

  • Associations suggested from clinical observations include renal transplantation, immunosuppressive agents, corticosteroid use, and obesity.

  • Systemic inflammation appears to be a predisposing factor. [12, 13]

The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism. Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.

Case reports exist of calciphylaxis occurring in primary hyperparathyroidism, cirrhosis, Crohn disease, malignancy, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain. [25, 22, 26, 27] The exact role of PTH is uncertain because calciphylaxis may occur after total parathyroidectomy, in the absence of measurable PTH levels.

Patients at an increased risk appear to be those who are obese and those who have been exposed to immunosuppressive agents, including glucocorticoids. [22] Calciphylaxis occurs more frequently in areas where body fat is most abundant, such as the thighs, the buttocks, and the lower part of the abdomen. [23, 24] Fatty areas may be at higher risk for thrombosis, owing to lower blood flow or the increased potential for vascular kinking.

Persons with diabetes mellitus may also be at an increased risk; [22, 23, 24] insulin injections may be an independent risk due to trauma to the subcutis.

The clinical appearance of the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggests that the common endpoint of the process is small vessel occlusion. Indeed, microthrombi are found in most cases.

Hypercoagulable conditions, including protein C and protein S deficiencies, and the presence of a circulating anticoagulant have been described in a number of patients. [28, 29, 30, 31, 32] However, conditions of hypercoagulability are not found uniformly. If they do exist, they could possibly precipitate or exacerbate calciphylaxis in a predisposed patient.

Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, various pathologic roles may be attributed to this vascular calcification. First, calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability. Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. Finally, data suggest that the uremic milieu may promote calcification through inhibition of various endogenous inhibitors of calcification such as alpha2-Heremans-Schmid glycoprotein/fetuin A (AHSG), osteopontin, and matrix Gla protein. These theories remain speculative. [8, 11]

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Epidemiology

Frequency

Calciphylaxis is an uncommon condition that affects 1-4% of the population with ESRD. [18, 19] A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran. No good data are available regarding the incidence of calciphylaxis in the general population without ESRD, but it is even less common. Nonuremic disease is being identified more commonly, especially in patients with rapid weight loss. Some cases are associated with warfarin use, but that association does not appear to alter prognosis. [20]

Race

Although the disease may affect persons of any race, it appears to be more prevalent in whites.

Sex

Females are affected more often than males, with a female-to-male ratio of approximately 3:1. Females also appear to be more commonly affected with nonuremic calciphylaxis.

Age

Calciphylaxis has been reported in individuals ranging in age from 6 months to 83 years. From a large series of patients, a mean patient age of 48 years (±16 y) has been calculated. Individuals seemingly more predisposed are younger patients who have had a longer duration of renal replacement therapy.

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Prognosis

The prognosis is generally not good, with a mortality rate as high as 60-80% in patients with ulcerative disease. [9] The mortality rate is higher in patients with proximal disease than in those with only distal or acral disease. Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases and intervention may be too late. [9] Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively. A multidisciplinary approach with debridement, parathyroidectomy, and aggressive medical management may improve survival. [6] The impact of sodium thiosulfate on overall survival rate is yet to be determined. [21]

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Patient Education

Emphasize compliance with the dialysis prescription. Educate patients regarding dietary restrictions and the need for phosphate binders. If anticoagulation is chosen, explain the risks and the benefits of this therapy.

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